Cancer, in one form or another, is a leading cause of death, and claimed the lives of more than 7.6 million people worldwide in 2008, according to the compiled statistics by WHO (WHO: http://www.who.int/mediacentre/factsheets/fs297/en/index.html; retrieved on 28 Apr., 2012). It is estimated that the annual death toll will reach 13.1 millions by 2030. Although numerous cancer chemotherapeutics are available today, they often have very narrow therapeutic indices and very severe side effects. In addition, cancers can and often do develop resistance to many of these drugs. The fact that there currently are no drugs available that are capable of curing cancer diseases, the discovery and development of new anticancer drugs are very much needed and the undertaking of such studies is imperative.
In a continuing drug discovery program, over 8,000 plant and microbial extracts for anticancer activity have been evaluated using a panel of cancer cell lines, resulting in the discovery of dozens of active lead molecules. Among these active leads are a series of promising compounds belonging to a cluster of novel molecules with a rare C-18 skeleton, which we designated collectively as “miliusanes”. These compounds were isolated from the leaves, twigs and flowers of Miliusa sinensis Finet and Gagnep. (Annonaceae) through bioassay-guided fractionation. Of the 22 miliusane isolates, 20 are new molecules. Ten of these compounds demonstrated tumor cell killing activity in a panel of cell lines (see FIG. 1) (Zhang H J, Ma C Y, Hung N V, Cuong N M, Tan G T, Santarsiero B D, Mesecar A D, Soejarto D D, Pezzuto J M, Fong H H S. Miliusanes, a class of cytotoxic agents from Miliusa sinensis. Journal of Medicinal Chemistry 2006; 49: 693-708).

Miliusol, miliusate as well as miliusane I were further evaluated in the NCI 60 cell line panel (see FIGS. 2 and 3). The mean GI50 values for the three compounds are 0.78 (0.17-2.29), 0.65 (0.034-3.31) and 0.74 (0.12-4.79) μM, respectively. The automated COMPARE analysis showed that the three compounds have similar GI50 response patterns in the NCI 60 cancer cell lines, indicated the similar anticancer mechanism of action of the three compounds. However, when comparing the three miliusanes with the other compounds in the NCI database, we do not find similar cell killing response pattern. The COMPARE negative thus raises further interests for the development of the miliusanes as potent anticancer drug candidates with a potential unique mechanism.
In an attempt to improve the anticancer activity of miliusanes, we prepared 42 miliusane derivatives with miliusol as the starting molecule such as the compounds of formula (V). Many of the miliusol derived compounds showed equivalent activity to miliusol itself, and a number of them demonstrated superior activity to the mother molecule (see FIG. 4) (Zhang H J, Ma C Y, Hung N V, Cuong N M, Tan G T, Santarsiero B D, Mesecar A D, Soejarto D D, Pezzuto J M, Fong H H S. Miliusanes, a class of cytotoxic agents from Miliusa sinensis. Journal of Medicinal Chemistry 2006; 49: 693-708).

Miliusanes are considered as a group of compounds containing a substructure of oxo-spirodecane. A few patents have been published related to the compounds containing oxospirodecane or azaspirodecane or thiaspirocecane substructure (US 2009/0318548A1; US2011/021624A1 and WO2011098433A1).
In US 2009/0318548A1, the compounds of formula (VI) were synthesized. However, no anticancer data were reported in this patent.

In US2011/021624A1, the compounds of formula (VII) were synthesized. However, the representative compound was reported to show weak cytotoxicity against MDA-MB-435, HCT116, A549 and Hela cancer cells (IC50 values in the range of 17-42 μM).

In WO2011098433A1, the compounds of formula (VIII) were synthesized. The compounds have a chemical structure containing a biphenyl group, and were reported to have tumor inhibition activity by inhibiting fatty acid synthesis.

Thus, miliusanes compounds with an improved anticancer activity and low in toxicity are needed.
Citation or identification of any reference in this section or any other section of this application shall not be construed as an admission that such reference is available as prior art for the present application.